Chemical reactions in compressed carbon dioxide

ABSTRACT

A palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide is provided wherein at least one of the reagents used in said reaction is bounded to a solid polymer support. In a second aspect, a palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide is provided wherein said reaction is performed in the presence of a tetra-alkylammonium acetate. In a third aspect, a palladium-catalysed carbon-carbon bond forming reaction in compressed carbon dioxide is provided wherein said palladium catalyst does not have any fluorinated phosphine ligands but does have at least one phosphine ligand that has at least one substituent that is selected from tert-alkyl groups, cycloalkyl groups and optionally substituted phenyl groups or 1′-diphenylphosphino-biphenyl. In a fourth aspect, there is provided a palladium-catalysed Suzuki or Heck reaction in compressed carbon dioxide wherein both of the substrates being combined in said reactions are boronic acids.

FIELD OF INVENTION

The present invention relates to palladium-catalysed cartoon-carbon bondforming reactions in compressed carbon dioxide.

BACKGROUND TO THE INVENTION

Supercritical carbon dioxide has been used for polymer synthesis andpolymer processing. This has been extensively reviewed in the past andthe state of the art is summarised in an article by Cooper [A. I.Cooper, J. Mater. Chem., 2000, 10, 207]. Compressed carbon dioxide isalso used as a solvent for the preparation of organic molecules and thishas been summarised in a special issue of Chemical Reviews. [see SpecialIssue: Chem. Rev. 1999, 99, #2]. Unlike conventional liquid solvents,carbon dioxide is highly compressible and the density (and thereforesolvent properties) can be tuned over a wide range by varying thepressure [see M. McHugh et al. “Supercritical Fluid Extraction” Boston,Butterworth-Heinemann, 1994]. Compressed carbon dioxide is an attractivealternative to conventional solvents because it is inexpensive,non-toxic and non-flammable. Compressed carbon dioxide reverts to thegaseous state upon decompression, simplifying solvent separation fromsolute(s) and reaction products.

Metal-catalysed processes are extremely common in the synthesis of smallorganic molecules for the pharmaceutical industry as well as foragrochemicals, flavours, fragrances and specialist consumer products.They are assuming growing importance in the synthesis of macromolecules,particularly conjugated polymers (see for example Bernius, M. T.;Inbasekaran, M.; Brien, J.; Wu, W. Adv. Mater., 2000, 12, 1737).

Metal-catalysed homogeneous reactions in supercritical carbon dioxidehave been reported and the state of the art is summarised in a specialedition of Chemical Reviews, 1999, 99(#2) and in a monograph “Chemicalsynthesis using supercritical fluids” P. G. Jessop and W. Leitner,Wiley-VCH, Weinheim, 1999. A comprehensive review of organic synthesisin supercritical carbon dioxide bas been written by Oakes, R. S.;Clifford, A. A.; Rayner, C. M. J. Chem. Soc., Perkin 1, 2001, 917.WO-A-98/32533 discloses the use of phosphorus ligands carryingperfluoroalkyl chains to solubilise rhodium phosphine complexes inhydroformylation and hydrogenation reactions. WO-A-99/38820 disclosesthe use of ligand-metal complexes in which the complex comprises aperfluorinated group for the transformation of organic molecules. Insome of the reactions, the substrate was anchored to a solid polymersupport. Palladium-catalysed cross coupling reactions in supercriticalcarbon dioxide have been disclosed (M. A. Carroll. M. A.; Holmes A. B.Chem. Commun., 1998, 1395; Morita, D. K; Pesiri, D. R; David, S. A.;Glaze, W. H.; Tumas, W.; Chem. Commun., 1998, 1397; Shezad, N., Oakes,R. S., Clifford, A. A. and Rayner, C. M., Tetrahedron Lett., 1999, 40,2221). The first mentioned paper reported Heck, Suzuki (Suzuki, A inMetal-catalysed Cross-coupling reactions, eds. Diederich, F. and Stang,P. J., Wiley-VCH, Weinheim, 1997.) and Sonogashira reactions. The secondreported, in addition, Stille reactions while the third reported the useof palladium(II) trifluoroacetate as the catalyst source. These examplesteach that perfluorinated alkyl ligands (or trifluoroacetate) areneeded, presumably for enhancement of solubility of the complex insupercritical carbon dioxide (sc CO₂). Non-fluorinated triarylphosphineshave been shown to lead to lower conversions in the Heck reaction (thepalladium-mediated addition of an aryl or vinyl halide to an alkene withregeneration of the double bond in the original alkene partner; seePalladium reagents in organic synthesis”, R. F. Heck, Academic Press,Orlando, 1985; Heck, R. F., Org. React., 1982, 27, 345; Beletskaya, I.;Cheprakov, Chem. Rev., 2000, 100, 309). Exceptionally, ring closingolefin metathesis (R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54,4413-4450) with an insoluble diphenylalkylidene ruthenium catalyst hasbeen realised. (Fürstner, A. et al. Angew. Chem. Int. Ed., 1997, 36,2646).

SUMMARY OF THE INVENTION

An important aspect of all the above palladium-mediated carbon-carbonbond forming reactions was the need for a solubilisingfluorine-containing phosphine ligand or a trifluoroacetate counterion tofor a homogeneous solution of the palladium complex in compressed carbondioxide. WO-A-99/38820 discloses the use of perfluorinatedligand-palladium complexes in which some of the reactions were performedusing a substrate which was anchored to a solid polymer support. It hasnever been previously disclosed or suggested however, that it might bepossible to perform palladium-mediated carbon-carbon bond formingreactions in compressed carbon dioxide using reagents that are anchoredto a solid polymer support. We have now made the surprising discoverythat it is possible to perform such palladium-mediated reactions incompressed carbon dioxide using reagents immobilised on commerciallyavailable solid supports. This gives many advantages, includingincreased ease of processing making it attractive as a potential meansof performing these reactions on an industrial scale and the discoverythat using such reagents it is possible to obtain excellent yieldswithout the need for a fluorinated phosphine ligand.

Thus, in a first aspect of the present invention there is provided apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent wherein at least one of the reagents used insaid reaction is bound to a solid polymer support.

By compressed carbon dioxide, we mean carbon dioxide which has beencompressed under pressure to produce liquid carbon dioxide orsupercritical carbon dioxide. A supercritical fluid may be defined as asubstance for which both the temperature and pressure are above thecritical values for the substance and which has a density close to orhigher than the critical density. Carbon dioxide is an ideal solventbecause of its mild critical temperature (31.1° C.) and its relativelylow critical pressure (73.8 bar). Another advantage of carbon dioxide isthat it is a gas under atmospheric conditions so that the end-reactionmixture is solvent-free.

By reagents we mean agents that are used to enable thepalladium-catalysed reaction to be performed but which do not includethe actual substrates that are being coupled in the carbon-carbon bondforming reaction. Examples of the polymer-bound reagents includepolymer-supported bases and polymer-supported solubilising ligands. Bysolubilising ligands we mean reagents that can interact with the sourceof palladium in the reaction and, as a result, increase the solubilityof the palladium in the compressed carbon dioxide.

Typical examples of the polymer-supported bases includepolymer-supported amine bases such as polymers hang supportedmonoalkylaminoalkyl groups and polymers having supporteddialkylaminoalkyl groups wherein each alkyl group is the same ordifferent and preferably has from 1 to 6 carbon atoms. Typical examplesof the supporting polymer include polystyrenes and macroreticular resins(e.g. Amberlyst®). Preferred examples of the polymer-supported basesinclude dialkylaminoalkylpolystyrene and dialkylamino-macroreticularresin, of which diethylaminomethylpolystyrene,diethylaminomethyl-Amberlyst resin and adisopropylmethylaminopolystyrene are more preferred anddiethylaminomethylpolystyrene is most preferred. Further examples ofsuitable polymer-supported bases are found in the review by S. V. Ley etall J.C.S. Perkin Trans. I, 2000, 3815. Using polymer-supported basessuch as these we have found that it is even possible to performpalladium-catalysed carbon-carbon bond forming reactions without theneed for the addition of a phosphine ligand to the palladium source.

Typical examples of polymer-supported solubilising ligands arepolymer-supported phosphine ligands. Typical examples of the supportingpolymer include polystyrenes and macroreticular resins (e.g.Amberlyst®). The phosphine ligands include ones that have at least onefluoro-substituted aliphatic or aromatic substituent such as phosphinesthat have at least one C₁-C₂₀ perfluoroalkyl substituent such as a1H,1H,2H,2H-perfluorooctyl group but also include ones that do not haveat least one fluorinated substituent but instead have substituents suchas alkyl groups (e.g. alkyl groups having from 1 to 6 carbon atoms,especially t-alkyl), cycloalkyl groups such as those having from 3 to 8carbon atoms and aryl groups such as phenyl groups which can besubstituted with at least one alkyl group having from 1 to 6 carbonatoms. Preferred examples include polymers having supporteddiarylphosphinoalkyl groups, polymers having supporteddialkylphospinoalkyl groups and polymers having supporteddicycloalkylphospinoalkyl groups wherein the alkyl, cycloalkyl and arylgroups are as defined above. More preferred examples includepolystyrenes and macroreticular resins having supporteddiphenylphosphinoalkyl groups, and the most preferred example isdiphenylphosphinomethylpolystyrene. Polymer-supported phosphines arewell-known in the art and are discussed, for example, in Trost et al, J.Am. Chem. Soc., 1978, 100, 7779, and Jang, Tetrahedron Lett., 1997, 38,1793, and can be obtained commercially (e.g. from Nova Biochem).

Not only is there significant potential for catalyst recyclability (asthe palladium is anticipated to remain on the resin) but these reactionscould potentially be monitored by on line procedures.

During our work, we have found that polymer-supported reagents such aspolymer supported bases and polymer-supported solubilising phosphinesallow completely heterogeneous Heck and Suzuki coupling reactions to becarried out in compressed carbon dioxide. Based on this observation, allpolymer-supported reagents should show significant enhancements inrates, reactivity and yields when used in these palladium-mediatedcarbon-carbon bond forming reactions. Examples of reactions which canall show improved yields through the use of polymer-supported reagentsinclude Heck reactions (e.g. see “Palladium reagents in organicsynthesis”, R. F. Heck, Academic Press, Orlando, 1985; Heck, R. F., Org.React., 1982, 27, 345; and Beletskaya, I.; Cheprakov, A. Chem. Rev.,2000, 100, 309), Suzuki reactions (e.g. see Migaura et al, Syn. Commun,1981, 11, 513), Sonogashira reactions (e.g. see Sonogashira et al,Tetrahedron Lett, 1983, 4467) and Stille reactions and relatedreactions.

As one example, we found that for the Heck reaction the addition of aryliodide and bromide substrates to acrylates such as butyl acrylate wassurprisingly effective using the combination of a palladium (0) sourcesuch as palladium (II) acetate and a polymer-supported base. Suitablepolymer-supported bases are of the type described and exemplified above,of which we found that ones selected from diethylaminomethylpolystyrene,a diethylaminomethyl-Amberlyst resin and adisopropylmethylaminopolystyrene are preferred anddiethylaminomethylpolystyrene is most preferred. Using these bases, wefound that no solubilising phosphine ligand is required at all. Forcarbon-carbon bond forming reactions such as the Heck reaction to haveuseful application in the pharmaceutical industry, it is essential thatthe phosphine content and the fluorine-substituted solubilising groupsshould be kept to a minimum. Clearly, the ability to perform thesereactions with no phosphine ligands or fluorine-substituted solubilisinggroups in some circumstances makes the process of the present inventionhighly promising. Furthermore, an inherent feature of this invention isthat the heterogeneous reaction with palladium catalyst leaves thecatalyst embedded in the polystyrene matrix. Experiments, using therecycled resin, are encouraging. This invention therefore shows thepotential for a continuous flow process using recycled palladium/resin.

Again using the Heck reaction as an example, although the combination ofsimple Pd (II) salts such as palladium acetate and aryl halides had beenpreviously used in the phase-transfer catalysis version of the Heckreaction (Jeffery, T. Tetrahedron 1996, 30, 10113), we have surprisinglyfound that the Heck addition of aryl iodides or bromides to an acrylatesuch as butyl acrylate can be realised in the presence of apolymer-supported solubilising phosphine ligand. Suitablepolymer-supported phosphine ligands are of the type described andexemplified above, of which diphenylphosphinomethylpolystyrene isparticularly preferred. The Heck addition using a palladium source suchas palladium (E) acetate in the presence of a polymer-supported phospineligand is best performed in the presence of a base or another promotingadditive, preferred examples of such bases and additives including:diisopropylethylamine, cesium carbonate, polymer-supported bases of thetype described above such as diethylaminomethylpolystyrene, sodiumacetate, sodium trifluoroacetate, triethylamine, tri-n-butylamine,perfluorinated trihexylamine, polystyrenemethylammonium carbonate,tetramethylethylamine diamine (TMEDA), tetramethylhexanediamine, andtetraalkylaminonium acetates such as tetrabutylammonium acetate. Ofthese, we prefer diisopropylethylamine and tetaalkylammonium acetates.Most preferably the additive is tetrabutylammonium acetate.

The combination of tetrabutylammonium chloride in the palladium-mediatedStille reaction with various phosphine ligands in super critical CO₂ hasbeen reported (Osswald, T.; Schneider, S.; Wang, S.; Bannwarth, W.Tetrahedron Lett, 2001, 42, 2965). This teaches the use of thisadditive, but surprisingly we have now found that tetra-alkylammoniumacetates give significantly superior yields in palladium-catalysedcarbon-carbon bond forming reactions.

Thus, in a second aspect of the present invention, there is provided apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent wherein said reaction is performed in thepresence of a tetra-alkylammonium acetate. Each alkyl group can be thesame or different and typically has from 1 to 6 carbon atoms, of whichalkyl groups having from 1 to 4 carbon atoms are more preferred.Preferred are tetraethylammonium acetate and tetra(n-butyl)ammoniumacetate, of which tetra(n-butyl)ammonium acetate is particularlypreferred.

We have surprisingly found that the yields in palladium-catalysedcarbon-carbon bond forming reactions are significantly superior when atetra-alkylammonium acetate is added to the reaction mixture in place ofthe known tetra-alkylammonium chlorides. While not wishing to be boundby theory, we believe that the role of the tetra-alkylammonium acetatesis probably related to interfacial catalysis.

Typically, the palladium-mediated carbon-carbon bond forming reaction isconducted using a solubilising ligand such as a phosphine ligand.Examples include include ones that have at least one fluoro-substitutedaliphatic or aromatic substituent such as phosphines that have at leastone C₁-C₂₀perfluoroalkyl substituent such as a 1H,1H,2,2H-perfluorooctylgroup but also include ones that do not have at least one fluorinatedsubstituent but instead have substituents such as alkyl groups (e.g.alkyl groups having from 1 to 6 carbon atoms, especially t-alkyl),cycloalkyl groups such as those having from 3 to 8 carbon atoms and arylgroups such as phenyl groups which can be substituted with at least onealkyl group having from 1 to 6 carbon atoms. Preferred examples includetri(t-butyl)phosphine, tri(cyclohexyl)phosphine, tri(o-tolyl)phosphineand 1′-diphenylphosphinobiphenyl. Particularly preferred, however, arepolymer-supported solubilising ligands such as the polymer-supportedphosphines described and exemplified above. Of these, we particularlyprefer polystyrenes and macroreticular res having supporteddiphenylphosphinoalkyl groups, and the most preferred example isdiphenylphospinomethylpolystyrene.

The use of tetra-alkylammonium acetates at elevated temperatures leadsto a two-phase reaction medium involving the molten ammonium salt as onecomponent. A further aspect of this invention is that the tetra-alkylammonium salts (e.g tetraethyl) may be used as hydrates and thetetra-alkylammonium salts such as the acetates may be used as 1M aqueoussolutions, providing a multiphase reaction medium for the actualcarbon-carbon bond forming reactions.

A feature of the first aspect of the invention using polymer-supportedreagents is the, ease of isolation of product. This follows from asimple washing of the reaction cell with compressed carbon dioxide whichselectively removes the small molecule product from the solid phasereactants. In the case of the Suzuki reaction it has been demonstratedthat the biaryl product can be simply isolated by washing and extractionin compressed carbon dioxide, followed by venting the pressure. Thisoperation shows considerable promise for continuous flow manufacturingin small bore carbon dioxide reactors where the catalyst and an aminesalt remain behind in the reactor vessel and the product is enacted bycarbon dioxide. It is also expected that this process should be equallypossible using the tetralkylammonium additive technique.

Thus, in a preferred embodiment of the present invention, there isprovided a palladium-mediated carbon-carbon bond forming reactionaccording to the first or second aspects of the present inventiondefined and exemplified above wherein said reaction is conducted as acontinuous flow reaction. Surprisingly the delivery of the reagents andcompressed CO₂ solvent through a mixing nozzle into a reaction tube,previously charged with the catalyst, leads to an extremely rapidchemical reaction under conditions above the critical temperature andpressure. The products and unconverted starting materials emerge fromthe reactor through a filter. The rate of flow of the products may becontrolled, for example, by the use of a back pressure regulator. Thisprocedure can be applied to Suzuki reactions (e.g. an aryl halidecoupled with a boronic acid), Heck reactions (e.g. an aryl halidecoupled with an olefin), Sonogashira reactions (e.g. an aryl halidecoupling with an alkyne) and Stille reactions (e.g. an aryl halidecoupled with an organostannane). Most preferably the Suzuki reaction canbe carried out under continuous flow conditions. Rapid formation ofproduct is observed even when the reactants are subject to a single passthrough the reactor, involving a short residence time in contact withthe catalyst. A co-solvent may be employed to assist in the charging ofthe reactor with some reagents. Preferred co-solvents include methanoland toluene, but any selection of common solvents, including fluorinatedsolvents may be used.

As discussed above, it has previously been believed that phospineligands having highly fluorinated substituents or trifluroacetatecounterions were needed to enable palladium-catalysed carbon-carbon bondforming reactions to be performed in compressed carbon dioxide withacceptable yields. For example, previously the electron richtri(2-furyl)-phosphine had been employed as a non-fluorinated ligand butwith low yields (Morita, D. K.; Pesiri, D. R.; David, S. A; Glaze, W.H.; Tumas, W.; Chem. Commun., 1998, 1397). Surprisingly, we have nowfound that a range of non-fluorinated phosphine ligands in combinationwith a palladium (0) source such as palladium (II) acetate catalysecarbon-carbon bond forming reactions more efficiently than thecombinations employing fluorinated phosphines.

Thus, in a further aspect of the present invention there is provided apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent wherein said palladium catalyst does nothave any fluorinated phosphine ligands but does have at least onephosphine ligand that has at least one substituent that is selected fromthe group consisting of tert-alkyl groups having from 4 to 10 carbonatoms, cycloalkyl groups having from 3 to 8 carbon atoms and phenylgroups which can be substituted with at least one alkyl group halingfrom 1 to 6 carbon atoms or 1′-diphenylphosphinobiphenyl.

The solubility of triethylphosphine in compressed CO₂ and its use incertain hydroformylation reactions has previously been described byCole-Hamilton (Bach, I.; Cole-Hamilton, D. J. Chem. Commun., 1998, 1463)but there has never previously been any suggestion thattert-alkylphospine solubilising groups might give superior results toperfluorinated alkylphospine solubilising groups in palladium-catalysedcarbon-carbon bond forming reactions.

Preferred examples of tert-alkyl substituents for the phosphine ligandsinclude tert-butyl groups, preferred examples of the cycloalkylsubstituent are cyclohexyl groups and preferred examples of theoptionally substituted phenyl groups are o-tolyl groups. Preferredphosphines include tri(t-butyl)phosphine, tri(cyclohexyl)phosphine,tri(o-tolyl)phosphine and 1′-diphenylphosphinobiphenyl groups. The mostpreferred phosphine ligand is tri(t-butyl)-phosphine.

The palladium source used as the catalyst is any suitable source ofpalladium (0). Preferred examples include palladium (II) acetate (byacetate we include both acetate per se and fluorinated acetates suchtrifluroacetate)

The Suzuki cross coupling of aryl bromides and iodides is effected incarbon dioxide in the presence of a palladium (0) source such palladium(II) acetate, non-fluorinated phosphines of the type defined andexemplified above [preferably selected from tri(t-butyl)phosphine,tri(cyclohexyl)phosphine, tri(6-tolyl)phosphine and1′-diphenylphosphinobiphenyl] and a base or other reaction-promotingadditive. Preferred examples of bases and other reaction-promotingadditives include diisopropylethylamine, cesium carbonate,diethylaminomethylpolystyrene, sodium acetate, sodium trifluoroacetate,triethylamine, tri-n-butylamine, perfluorinated trihexylamine,polystyrenemethylammonium carbonate, tetramethylethylenediamine diamine(TMEDA), tetramethyl hexanediamine, and tetraalkylammonium acetates suchas tetrabutylammonium acetate. Preferred bases are tetramethylhexanediamine and cesium carbonate, the former being surprisinglysoluble in compressed carbon dioxide. As alternatives to a base, thepreferred reaction-promoting additives are tetra-alkylammonium acetates,particularly tetra(n-butyl)ammonium acetate.

An added feature of this invention is the use of biphasic conditions,for example the combination of water, methanol or isopropanol withcompressed carbon dioxide. Water is preferred. For example, thecombination phenyl boronic acid, bromobenzene, cesium carbonate,palladium (II) acetate, phosphine, and water (10 vol %) produce biphenylin excellent yield. The second phase enhances the basicity of the baseadditive. The enhanced activity in the presence water is particularlysurprising.

Substrates are not limited to aromatic halides and boronic acids nor toacrylates. All sp²-substituted reagents which are potential crosscoupling partners may be selected for this invention.

WO-A-99/38820 discloses the Heck reaction of an acrylate REM resin(Morphy, J. R.; Rankovic, Z.; Rees, D. C. Tetrahedron Lett. 1996, 37,3209). Surprisingly such substrates undergo Heck reactions in thepresence of palladium (II) acetate and non-fluorinated phosphines of thetype defined and exemplified above [preferred examples being selectedfrom tri(t-butyl)phosphine, tri(cyclohexyl)phosphine,tri(o-tolyl)phosphine and 1′-diphenylphosphinobiphenyl] and a base orother reaction-promoting additive (preferred examples being selectedfrom diisopropylethylamine, cesium carbonate,diphylaminomethylpolystyrene, sodium acetate, sodium trifluoroacetate,triethylamine, tri-n-butylamine, perfluorinated trihexylamine,polystyrenemethylammonium carbonate, tetramethylethylenediamine diamine(TMEDA), tetramethyl hexanediamine, and tetraalkylammonium acetates suchas tetrabutylammonium acetate. Most preferably the combination palladium(II) acetate, tri(z-butyl)phosphine, iodobenzene, diisopropylethylamineand the acrylate REM resin in compressed carbon dioxide afforded after,cleavage from the resin, cinnamic acid in 98% yield.

Similarly, we also found that Suzuki cross coupling reactions of aselection of halo-vinyl and iodo- and bromo-aryl substituted compoundsattached to a Merrifield or Wang resin through an ester linker can beeffected with reagents selected from a list of aryl and vinylboronicacids and the above ligand-base-catalyst combinations. Most preferablythe combination palladium (II) acetate, tri(t-butyl)phosphine,4-iodobenzenecarboxylic (ester link to Merrifield resin),4-methylbenzeneboronic acid and diisopropylethylamine gave4′-methylbiphenyl-4-carboxylic acid in excess of 80% yield.

Thus, based on these findings, it is a preferred feature of all threeaspects of the present invention that the palladium-mediatedcarbon-carbon bond-forming reactions in compressed carbon dioxide as asolvent are conducted using at least one substrate of the carbon-carbonbond-forming reaction that is bound to a solid polymer support. Examplesof suitable polymer supports are the same as those discussed above forthe polymer-supported bases and reagents.

Another surprising finding is that when Heck and Suzuki couplingprocedures are conducted according to the third aspect of the presentinvention, they are effective on aryl bromide substrates as well as aryliodides when the combination tri(t-butyl)phosphine and palladium (U)acetate is used.

We have also found that the palladium-mediated homo-coupling ofo-tolylboronic acid can be carried out in compressed carbon dioxide.This is an important and surprising advantage as halide ions arecorrosive for the stainless steel vessels necessary for carbon dioxideas solvent. Therefore Heck reactions may be carried out with reactiveboronic acids for the initial palladium insertion followed by couplingwith an sp²-partner. Initiation of Suzuki reactions with a reactiveboronic acid followed by cross coupling with a less reactive boronicacid should also be possible. Thus, in a further aspect of the presentinvention there is provided a palladium-catalysed Suzuki or Heckreaction in compressed carbon dioxide as a solvent wherein both of thesubstrates being combined in said reactions are boronic acids. Thereagents and reaction conditions may preferably be as defined andexemplified above for the first, second and third aspects of the presentinvention (e.g. the bases and solubilising ligands can be the solidpolymer-supported bases and solubilising ligands defined in the firstaspect of the invention, the reactions can be performed in the presenceof a tetra alkylammonium acetate as defined in the second aspect of thepresent invention and the reactions can be carried out using thenon-fluorinated phosphine ligands defined in the third aspect of thepresent invention).

BRIEF DESCRIPTION OF THE DRAWINGS

The present may be further understood by consideration of the followingembodiments of the present invention, with reference to the followingdrawing in which:

FIG. 1 is a flow diagram of a reactor for a Suzuki reaction carried outunder continuous flow conditions in accordance with one aspect of thepresent invention.

EXAMPLE 1 Heck Reactions Using Pd (II) Salts in Combination withNon-Fluorinated Phosphines

Tri-t-butylphosphine (20 mg, 0.1 mmol), palladium (II) acetate, (11 mg,0.05 mmol), iodobenzene (204 mg, 1 mmol), butyl acrylate (141 mg, 1.1mmol), and triethylamine (0.121 mg, 1.2 mmol), were placed in a 10 cm³stainless steel cell under an atmosphere of nitrogen. The cell wassealed, removed from the glove-box and connected to a purged carbondioxide line. The cell was then charged with carbon dioxide toapproximately 800 psi (two thirds full of carbon dioxide.) The suspendedreagents were magnetically stirred as the cell was heated to 100° C.,3000 psi. The reagents were stirred at this temperature and pressure for40 h and the cell was then allowed to cool to room temperature. Thecontents of the cell were vented into ether (100 cm³) and onceatmospheric pressure had been reached the cell was opened and washed outwith dichloromethane (20 cm³). The organic fractions were combined andconcentrated in vacuo to give the crude product. The product,trans-butyl cinnamate was purified by flash column chromatography onsilica gel, eluting with dichloromethane to give an off-whitecrystalline solid (160 mg, 78%). δH (250 MHz; CDCl₃) 7.68 (1H, d, PhCH═,J 16 Hz), 7.52-7.54 (2H, m, o-Ph), 7.37-7.39 (3H, m, m/p-Ph) 6.44 (1H,d, ═CHCOOBu, J 16 Hz), 4.21 (2H, t, OCH2, J 6.7 Hz), 1.69 (2H, m,OCH₂CH₂), 1.44 (2H, m, OCH₂CH₂CH₂), 0.97 (3H, t, CH₂CH₃ J 7.4 Hz).

Further Heck reactions were conducted in supercritical carbon dioxidefollowing the general process above using various halobenzenes andacrylate esters as the substrates, various bases, palladium (II) acetate(5 mol %) as the catalyst and and tri-t-butylphosphine (10 mol %). Theresults are as shown in Table 1 below. TABLE 1 Heck reaction of acrylateesters with halobenzenes using Pd(II) acetate (5 mol %) andtri-t-butylphosphine (10 mol %) in sc CO₂ Entry Halide Acrylate Base(1.2 equiv.) Time T/° C. Yield/% 1 Iodo Methyl DIPEA 16 h 100 77 2 IodoButyl DIPEA 16 h 100  92^(§) 3 Iodo Methyl Cs₂CO₃ 40 h 100 57 4 IodoMethyl NEt₃ 40 h 100 68 5 Iodo Butyl NEt₃ 40 h 100 78 6 Bromo MethylDIPEA 16 h 100 40 7 Chloro Methyl DIPEA 16 h 100 trace^(§)10 mol % catalyst Pd(II) and 20 mol % phosphine; DIPEA isdiisopropylethylamine

EXAMPLE 2 Heck Reactions of Aryl Halides with Butyl Acrylate in thePresence of Merrifield Phosphines

Diphenylphosphinomethyl polystyrene (obtained from Nova Biochem; 3.30 g,4.78 mmol 1.45 mmol/g based on manufacturer's loading) and palladiumacetate (226 mg, 1 mmol) were stirred in dichloromethane (50 ml) for 24h. The resulting resin was filtered (sinter), washed [dichloromethane(6×), ethanol (6×) diethyl ether (6×)] and dried to give 3.89 g ofresin. Bromobenzene (0.2 ml, 0.19 mmol), butyl acrylate (0.4 ml, 2.6mmol), tetra n-butylammonium acetate (1 g, 3.4 mmol) and the resin-boundpalladium catalyst (100 mg, 30 μmol Pd) were sealed in a stainless steelpressure vessel. The vessel was half-filled with liquid CO₂ (ca. 800psi) and the mixture was heated at 120° C. (ca. 3000 psi) for 16 h. Thecell was cooled and the CO₂ vented into a beaker containing ethylacetate. The remnants from the cell were washed (ethyl acetate) andpooled with the vented solution. The mixture was filtered and thesolvent was removed under reduced pressure to yield a residue (1.713 g).1,4-Dimethoxybenzene (370 mg) was added as an internal standard and themixture was dissolved in acetonitrile. The solution was diluted so thatthe final concentration of standard was less than 1 mg/ml. HPLCdetermination of the yield of the product n-butyl cinnamate was 100%.

Calibration of the product and internal standard had previously beencarried out in a separate experiment. Experiments were carried out aSupelcosil ABZ+ (330×4.6 mm, 3 μm particle size) column: Initial 19:1%water/acetonitrile

1:19 water/acetonitrile over 10 min at a rate of 1 ml min⁻¹.

A similar procedure was carried out using different halobenzenes andbases/additives according to Scheme 2 below. The results are shown inTable 2.

Scheme 2 illustrates the use of polymer supported phosphines asexemplified in Table 2.

TABLE 2 Pd(OAc)₂ Temp Entry X mol % Base or Additive ° C. Time h Yield %1 Br 3

120 16  41^(a) 2 Cl 3

120 16  2^(a) 3 Br 3

100 16  14^(a) 4 Br 3

80 16  4^(a) 5 I 3

80 16  84 6 Br 3 (C₄H₉)₄NOAc 120 16 100^(a) 7 Br 3 (C₂H₅)₄NOAc.4H₂O 12016 >80^(a) 8 Br 3 (C₄H₅)₄NOAc.4H₂O 100 16  30^(a) 9 Br 3 (C₄H₉)₄NCl 10016  21^(a)^(a)Yield determined by HPLC using internal standard(1,4-dimethoxybenzene)

These results demonstrate clearly that excellent yields can be obtainedusing polymer-supported phosphine ligands that contain no fluorine. Theresults obtained when tetraalkylammonium acetates were used wereparticularly good and much better than those obtained with thecorresponding tetra-alkylammonium chloride.

EXAMPLE 3 Heck Reactions of Aryl Iodides with Butyl Acrylate UnderPhosphorus Free Conditions in the Presence of Polymer-Supported Amines

For cross-coupling reactions to have useful application in thepharmaceutical industry, it is essential that phosphine content be keptto a minimum. We performed a series of Heck reactions usingpolymer-supported amine bases to see whether it was possible to obtaingood yields in the absence of phosphine ligands.

Iodobenzene (0.35 ml, 3.1 mmol), palladium acetate (22 mg, 0.07 mmol),butyl acrylate (0.6 ml, 4 mmol) and diethylaminopolystyrene (1 g, 3.2mmol of active reagent) were placed in a 10 ml stainless steel pressurereactor. The sealed cell was charged with liquid carbon dioxide (dry andoxygen free) to a pressure of 1000 psi and the cell was heated at 100°C. for 16 h. The reaction was cooled, and the resulting dark green resinwas filtered whilst being rinsed with alternate amounts of ethyl acetateand ether. The combined solvents were removed under reduced pressure,and the residue was chromatographed on a flash silica gel column elutedwith ethyl acetate-hexane (1:19) to give (E)-butyl cinnamate (580 mg,95%).

Further Heck reactions were performed under similar conditions accordingto the general Scheme 3 below. The results of these experiments werehighly promising, as shown in Table 3 below.

TABLE 3 Solid supported Heck reactions carried out in the absence ofphosphine. Approx mol Temp Yield X R % Pd Time (h) (° C.) (%) 1 I 4-H 516 100 95^(a) 2 I 4-NO₂ 5 16 100 92^(a) 3 I 4-COMe 5 16 100 87^(a) 4 I4-OMe 5 72 100 78^(a) 5 I 4-OH 5 16 60 69^(a) 6 I 4-I 5 16 100 83^(a) 7I 2-OH 5 16 100 90^(b) 8 I 2-CH₂OH 5 16 100 60  9 Br 4-NO₂ 5 16 10093^(a)^(a)Yield based on recovery after chromatography;^(b)Irradiation of the crude reaction product, afforded coumarin in 70%yield.

The use of polymer supported amines facilitated the Heck reaction insupercritical carbon dioxide in the absence of either phosphine orfluorine-substituted solubilising groups. An inherent feature of thisinvention is that the heterogeneous reaction with palladium catalystleaves the catalyst embedded in the polystyrene matrix. This inventiontherefore shows the potential for a continuous flow process usingrecycled palladium/resin.

EXAMPLE 4

Suzuki Reactions of Arylboronic Acids with Pd(II) Acetate, aNon-Fluorinated Phosphine and Several Bases

4(a) Biphenyl

A 10 cm³ stainless steel cell was charged with iodobenzene (0.210 g,1.03 mmol), phenyl boronic acid (0.366 g, 3.0 mmol), palladium (II)acetate, (0.011 g, 0.05 mmol), tri(o-tolyl)phosphine (0.030 g, 0.10mmol), caesium carbonate (0.978 g, 3.0 mmol) and water (1 cm³). The cellwas then connected to the carbon dioxide line and charged with carbondioxide to approximately 460 psi (half full of carbon dioxide.) The cellwas heated to 120° C., and the pressure adjusted to 1650 psi by theaddition of more carbon dioxide. The reagents were stirred at thistemperature and pressure for 16 h and the cell was then allowed to coolto room temperature. The contents of the cell were vented into ethylacetate (100 cm³) and once atmospheric pressure had been reached thecell was opened and washed out with further ethyl acetate (50 cm³). Theorganic fractions were combined and washed with water (30 cm³) thenbrine (30 cm³) and dried over anhydrous magnesium sulphate. The filtratewas concentrated in vacuo to give the crude product which was purifiedby flash column chromatography on silica gel, eluting with hexane togive a white crystalline solid (0.143 g, 90%). mp 69-72° C. δH (250 MHz;CDCl₃) 7.60 (4H, d, o-Ph, J 7.8 Hz), 7.45 (4H, dd, m-Ph, J 7.8, 7.2 Hz),7.35 (2H, t, p-Ph, J 7.2 Hz). δC (400 MHz; CDCl₃) 141.26 (quaternary Ph)128.74 (m-Ph), 127.25, 127.17 (o/p-Ph).

4(b) 4-Nitrobiphenyl

A 10 cm³ stainless steel cell was charged with 4-bromonitrobenzene(0.202 g, 1.00 mmol), phenyl boronic acid (0.122 g, 1.0 mmol), palladium(II) acetate, (0.002 g, 0.01 mmol), tricyclohexylphosphine (0.006 g,0.02 mmol) and caesium carbonate (0.326 g, 1.0 mmol). The cell was thenconnected to the carbon dioxide line and charged with carbon dioxide toapproximately 900 psi (half fill of carbon dioxide.) The cell was heatedto 110° C., and the pressure adjusted to 3000 psi by the addition ofmore carbon dioxide. The reagents were stirred at this temperature andpressure for 16 h and the cell was then allowed to cool to roomtemperature. The contents of the cell were vented into ethyl acetate(100 cm³) and once atmospheric pressure had been reached the cell wasopened and washed out with further ethyl acetate (50 cm³). The organicfractions were combined and concentrated in vacuo, then adsorbed ontosilica and purified by flash column chromatography on silica gel,eluting with 90:10 hexane:ethyl acetate to give 4-nitrobiphenyl as awhite crystalline solid (190 mg, 95%). δH (250 MHz; CDCl₃) 8.31 (2H, d,o-Ar, J 8.9 Hz), 7.74 (2H, d, m-Ar, J 8.9 Hz), 7.63 (2 H, d, o′-Ar), J6.9), 7.45-7.54 (3H, m, m′-Ar and p′-Ar). δC (250 MHz; CDCl₃) 147.6,147.1, 138.8, 129.2, 128.9, 127.8, 127.4, 124.1.

The two examples above demonstrate that the Suzuki reaction can beconducted using a triarylphosphine or tricycloalkylphosphine ligand togive a biaryl product such as that shown in Scheme 4 which can be simplyisolated by washing and extraction in compressed carbon dioxide,followed by venting the pressure. Further reactions were conducted usingaccording to this general procedure using other halobenzenes, boronicacids, bases and phosphine ligands, including a trialkylphosphineligand. The results are shown in Table 4 below. This operation showsconsiderable promise for continuous flow manufacturing in small borecarbon dioxide reactors where the catalyst and amine salt remain behindin the reactor vessel and the product is extracted by carbon dioxide.Tis process should be equally possible using the tetralkylammoniumadditive technique.

TABLE 4 Suzuki reaction of aryl halides with aryl boronic acids in thepresence of Pd(II) acetate (5 mol %) and various phosphines (10 mol %.)and bases (2 equiv.) Boronic Time/ T/ Yield/ Entry Halide acid PhosphineBase h ° C. % 1 Iodo Phenyl P(t-Bu)₃ DIPEA 16 100 68 2 Iodo TolylP(t-Bu)₃ DIPEA 16 100 73 3 Iodo Tolyl P(t-Bu)₃

16 120 76 4 Bromo Tolyl P(t-Bu)₃ DIPEA 16 100 54 5 Bromo Tolyl P(t-Bu)₃Cs₂CO₃ 16 100 52 6 Chloro Tolyl P(t-Bu)₃ DIPEA 64 100 19 7 Iodo PhenylP(o-tolyl)₃ Cs₂CO₃/H₂O 16 120 90 8 Bromo Phenyl P(o-tolyl)₃ Cs₂CO₃/H₂O64 110 96 9 Bromo Tolyl P(o-tolyl)₃ Cs₂CO₃/H₂O 16 110 73 10 Bromo PhenylP(cy)₃ Cs₂CO₃/H₂O 16 110 73 11 Bromo Phenyl P(cy)₃ Cs₂CO₃/H₂O 40 110 9012 Bromo Phenyl P(cy)₃ NBu₄OAc 16 110 72 13 Bromo Tolyl P(cy)₃ NBu₄OAc64 110 84

Buchwald (Old., D. W.; Buchwald, S. J. Am. Chem. Soc. 1998, 120, 9722)and Fu (Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 1998, 37,3387)have exploited tri-t-butylphosphine in a variety of cross-couplingreactions mediated by Pd(0). In this invention it has surprisingly beenfound that not only tri-t-butylphosphine, but alsotricyclohexylphosphine and tri-o-tolylphosphine can be used for thesuccessive promotion of Suzuki coupling reactions with Pd(OAc)₂ insupercritical carbon dioxide with aryl iodides, bromides, and chlorides,as is demonstrated in Table 4 above.

EXAMPLE 5 Heck Reactions on a Substrate Supported on Solid Phase

WO-A-99/38820 discloses the Heck reaction of an acrylate attached to aMerrifield resin on which solubilising fluorinated phosphines were usedto solubilise the palladium catalyst. This research has the potential toexploit the swellability of such resins and to carry out rapid parallelsynthesis and combinatorial chemistry with solid phase supportedsubstrates in supercritical carbon dioxide. Commercially available REMresin was treated with a variety of aromatic aryl iodides, Pd(II)acetate, and an ante base at either 40 or 80° C. These resultsdemonstrate the surprisingly efficient heterogeneous Heck couplingreaction with tri-t-butylphosphine as the ligand. The following gives anumber of fall worked example of the conditions used for the preparationof various cinnamic acids. A similar approach was then used for otherpalladium sources, bases, temperatures and reaction times as shown inTable 5.

(a) trans-Cinnamic Acid

Commercially available REM resin (500 ma, 0.44 mmol; obtained from NovaBiochem), iodobenzene (102 mg, 0.5 mmol), palladium trifluoroacetate (17mg, 0.05 mmol), diisopropylethylamine (0.1 ml, 0.55 mmol) andt-tributylphospine (28 mg, 0.14 mmol) were placed in a stainless steelcell and suspended in supercritical CO₂ at 40° C. for 40 h. After thistime, the cell was cooled and the product filtered, whilst washing withCH₂Cl₂ (6×), water (6×), EtOAc (3×) and Et₂O (3×)—to give the modifiedresin (632 mg). The resin (620 mg) was stirred in a KOH solution [3 ml,1.5M solution in TFA/MeOH/H₂O (2:2:1)] for 20 h. This was filtered andthe solvent removed under reduced pressure. The residue was redissolvedin ethyl acetate and was washed with dil. HCl (1M, water and brine. Thiswas dried (MgSO₄) and the solvent removed under reduced pressure. Theresidue was chromatographed (silica gel, ethyl acetate—toluene (2:8) asthe eluent) to give trans-cinnamic acid (58 mg, 93%). Solid phase IR ofthe remaining resin indicated complete saponification of the esterlinker.

(b) Trans-Cinnamic Acid

The REM resin (500 mg, 0.44 mmol 100-200 mesh), iodobenzene (0.12 ml,1.2 mmol), Pd(OAc)₂ (10 mg, 0.05 mmol), tri-1-butylphosphine (60 mg, 0.3mmol) and diisopropylethylamine (0.08 ml, 0.46 mmol) were sealed underan atmosphere of carbon dioxide (ca. 800 psi). The reaction was heatedat 80° C. for 16 h. The reaction was cooled and resin filtered through asinter whilst sequentially washing with dichloromethane (4×), H₂O (4×),EtOAc (6×) and diethyl ether (6×). The resin was stirred in a solutionof KOH (10 ml, 1.5 M solution in THF/H₂O/MeOH) for 16 h. The solutionwas acidified with dil. HCl (1 M) and the product extracted with EtOAc.The organic phase was washed (water, brine), dried (MgSO₄) and thereduced product chromatographed (silica gel, ethyl acetate-toluene(1:3)) to give cinnamic acid (66 mg, 98%).

(c) 4-Nitrocinnamic Acid

The REM resin (500 mg, 0.44 mmol), 4-nitroiodobenzene (125 mg, 0.5mmol), Pd(OAc)₂ (11 mg, 0.05 mmol), tri-t-butylphosphine (75 ml, 0.37mmol) and NEt₃ (0.3 ml, 2.8 mmol) were sealed under an atmosphere ofcarbon dioxide (ca. 800 psi). The reaction was heated at 80° C. for 16h. The reaction was cooled and the resin filtered through a sinterwhilst sequentially washing with dichloromethane (4×), H₂O (4×), EtOAc(6×) and diethyl ether (6×).

The resin was stirred in a solution of KOH (10 nm 1.5 M solution inTHF/H₂O/MeOH) for 16 h. The solution was acidified with dil. HCl (1 M)and the product extracted with EtOAc. The organic phase was washed(water, brine), dried (MgSO₄) and the solvent removed under reducedpressure to give the crude nitro product (90 mg, ca 100%).

(d) 4-Hydroxycinnamic Acid and 4-Acetylcinnamic Acid

The REM resin (1 g, 0.88 mmol), 4-iodophenol (110 mg, 0.44 mmol),4-iodoacetophenone (123 mg, 0.44 mmol), Pd(OAc)₂ (11 mg, 0.05 mmol),tri-t-butylphosphine (25 ml, 13 mmol) and NEt₃ (0.28 ml, 2.2 mmol) weresealed under an atmosphere of carbon dioxide (ca. 800 psi). The reactionwas heated at 80° C. for 16 h (Ca 1700 psi). The reaction was cooled andthe resin filtered through a sinter whilst sequentially washing withdichloromethane (4×), H₂O (4×), EtOAc (6×) and diethyl ether (6×). Theresin was dried (1.21 g).

The resin was stirred in a solution of KOH (10 ml, 1.5 M solution inTHF/H₂O/MeOH) for 16 h. The solution was acidified with dil. HCl (1 M)and the product extracted with EtOAc. The organic phase was washed(water, brine), dried (MgSO₄) and the solvent removed under reducedpressure. The residue was chromatographed (silica gel,methanol-dichloromethane 1:19 as the eluent) to give 4-hydroxycinnamicacid (42 mg, 58%) followed the acetophenone derivative (ca. 50 mg, 63%).

Using the approach set out in the above examples, the results for otherpalladium sources, bases, temperatures and reaction times are as shownin Table 5.

TABLE 5 Investigations into solid supported reactants in scCO₂ Time R PdSource Base (h) Temp (° C.) Yield (%) 1 H Pd(OCOCF₃)₂ NEt₃ 18 40 60^(a)2 H Pd(OCOCF₃)₂ NEt₃ 40 40 80^(a) 3 H Pd(OCOCF₃)₂ DIPEA 40 40 92^(a) 4 HPd(OCOCF₃)₂ NEt3 40 80 93^(a) 5 H Pd(OCOCF₃)₂ DIPEA 40 80 95^(a) 6 HPd(OAc)₂ DIPEA 16 80 98^(a) 7 NO₂ Pd(OAc)₂ NEt₃ 16 80 42^(b) 8 COMePd(OAc)₂ NEt₃ 16 80 70^(b)^(a)Yield determined by cleavage from resin after purification bychromatography;^(b)Yield from crude product NMR;^(c)All experiments were carried out with 10 mol % PdScheme 5 Heck reactions carried out on commercially available REM resin

Several aspects are noteworthy from the results in Table 5. Thesereactions are the first reactions of their kind to be carried out insupercritical CO₂. Changing the source of palladium did not influencethe yields to any great extent, however; it was noted that DIPEA(diisopropylethylamine) was a more effective base than triethylamine.The reactions are feasible at mild temperatures.

EXAMPLE 6 Suzuki Reactions on a Substrate Supported on Solid Phase

(a) Preparation of the Resins

(i) Merrifield resin [5 g, 6.2 mmol, 1.24 mmol/g based on manufacturersspecification (Nova Biochem)], p-bromobenzoic acid (2 g, 10 mmol),Cs₂CO₃ (1.51 g, 4.6 mmol) and KI (0.5 g, 3.0 mmol) in dimethylformamide(80 ml) were heated at 80° C. for 16 h. The cooled solution was filteredthrough a sinter whilst washing sequentially with EtOAc (3×), H₂O (3×),EtOAc (3×), dichloromethane (3×), ethanol (6×) and diethyl ether (6×).The residue was dried (5.8 g), δ_(max)/cm⁻¹ (FTIR solid phase) 1719(CO).

(ii) The identical reaction was carried out using p-iodobenzoic acidgiving similar results.

(iii) Wang Resin [3.09 g, 4 mmol, 1.3 mmol/g based on manufacturersspecification (Nova Biochem)], p-bromobenzoic acid (1.6 g, 8 mmol),diisopropyldiimide (1 ml, 6.4 mmol) and dimethylaminopyridine (DMAP) (48mg, mmol) in dichloromethane (50 ml) were stirred for 20 h. The residuewas filtered through a sinter whilst washing sequentially withdichloromethane (6×), H₂O (4×), dichloromethane (3×), EtOAc (6×),ethanol (6×) and diethyl ether (6×). The residue was dried (3.44 g);δ_(max)/cm⁻¹ (FTIR solid phase) 1720 (CO).

(b) Use of the Prepared Resins in Suzuki Reactions(i) 4 Phenylbenzoic Acid

The Merrifield resin prepared in (a)(i) above (500 mg, ca. 0.65 mmol),phenyl boronic acid (244 mg, 2.0 mmol), diisopropylethylamine (0.19 ml,1.1 mmol), Pd(TFA)₂ (33 mg, 0.1 mmol) and t-tributylphosphine (50 mg,0.26 mmol) were placed in a reaction cell and the cell sealed under anatmosphere of carbon dioxide (ca. 800 psi). The reagents were heated at80° C. for 40 h when the mixture was cooled. The resin was filteredwhilst washing sequentially with CH₂Cl₂ (6×), H₂O (6×), EtOAc (3×) andEt₂O (3×). The resin was dried to constant mass (460 mg); δ_(max)/cm⁻¹(FTIR solid phase) 1714 (CO). The resin thus obtained (440 mg) wasstirred in TFA/CH₁₂Cl₂ (1:1, 5 ml) for 6 h. This was filtered whilstwashing with CH₂Cl₂. The solvent was removed under reduced pressure andthe residue was chromatographed (silica gel, EtOAc/Toluene 3:7) to yieldthe biaryl product (80 mg, 68% over 3 steps)

(ii) 4-Tolylbenzoic Acid

The Merrifield resin prepared in (a)(i) above (1.8 g, ca. 2.2 mmol),4-tolyl boronic acid (500 mg, 3.6 mmol), diisopropylethylamine (0.2 ml,1.1 mmol), Pd(OAc)₂ (10 mg, 0.04 mmol) and t-tributylphosphine (100 mg,0.5 mmol) were placed in a reaction cell and the cell sealed under anatmosphere of carbon dioxide (ca. 800 psi). The reagents were heated at80° C. for 16 h when the mixture was cooled. The resin was filteredwhilst washing sequentially with CH₂Cl₂ (6×), H₂O (6×), EtOAc (3×) andEt₂O (3×). The resin thus obtained was stirred in a solution of KOH (10ml, 1.5 M solution in THF/H₂O/MeOH) for 16 h. The solution was acidifiedwith dil. HCl (1 M and the product extracted with EtOAc. The organicphase was washed (water, brine), dried (MgSO₄) and the solvent removedunder reduced pressure to give a mixture of starting material and biarylproduct (340 mg, 40% by NMR, >85% based on equivalents ofdiisopropylethylamine).

The results for reaction of freshly prepared iodobenzoate-modifiedMerrifield resin with commercially available boronic acids gavepromising results (Table 6)

Scheme 6 Reagents and conditions: (i) Pd(OAc)₂, P(t-Bu)₃, base, heat;(ii) KOH, MeOH, THF TABLE 6 Pilot Suzuki reactions of supportedreactants carried out in scCO₂ Pd Time Temp Entry R Pd Source (mol %)Base (h) (° C.) Yield (%) 1 H Pd(OCOCF₃)₂ 10 DIPEA 40 80 >65^(a) 2 MePd(OAc)₂ 5 DIPEA 16 80 >80^(a)^(a)Results are based on manufacturer's loading

The aforementioned reactions clearly demonstrate the successfulapplication of heterogeneous cross-coupling reactions of solid supportedsubstrates in compressed CO₂.

EXAMPLE 7

Continuous Flow Suzuki Reaction in Supercritical CO₂ of an Aryl Halidewith Phenylboronic Acid

A 50 cm³ stainless steel pressure reactor was fitted with a filter, andconnected to three stainless steel injection lines which werepressurised by HPLC pumps (see FIG. 1). An outlet (exhaust) line wasconnected via a back pressure regulator. The vessel was placed in anoven and was heated to 110° C. CO₂ was charged at a rate of 5 cm³/minuntil a pressure of 140 kg/cm² (137 bar) was reached. Once the settemperature and pressure were attained, methanol (5 cm³) was added at arate of 0.5 cm³/min over 10 minutes. Palladium acetate (0.011 g, 0.05mmol) and tricyclohexylphosphine (0.028 g, 0.10 mmol) were made up in asolution of methanol (5 cm³). This solution was added at a rate of 0.5cm³/min over 10 minutes, then further methanol (5 cm³) was added at thesame rate for a further 10 minutes. A solution of bromobenzene (0:162 g,1.03 mmol), phenylboronic acid (0.122 g, 1.00 mmol) andtetrabutylammonium acetate (0.301 g, 1.00 mmol) in methanol (20 cm³) wasprepared. The rate of CO₂ addition was adjusted to 2 cm³/min and thereagent solution was added at a rate of 0.1 cm³/min. Once addition wascomplete methanol (5 cm³) was added at the same rate of 0.1 cm³/min toflush the HLC line. Once this addition was complete the reactor wasdepressuzised. All exhaust from the vessel was vented through ethylacetate (150 cm³), which was collected, reduced in volume in vacuo andsubjected to column chromatography on silica gel eluting with 100%isohexane to give the product, biphenyl (0.078 g, 51%) as a whitecrystalline solid.

Further reagents were reacted under continuous flow conditions. Theresults are shown in Table 7 below. The surprising success of the Suzukicoupling of aryl bromides under conditions where the reagents are insuch short contact times with the catalyst is noteworthy. TABLE 7Continuous flow Suzuki reaction in scCO₂ of an aryl halide withphenylboronic acid using NBu₄OAc and a catalyst comprising Pd(OAc)₂/PCy₃Entry Aryl bromide Yield (%) 1 bromobenzene 51 2 4-bromofluorobenzene 653 4-bromoanisole 26

EXAMPLE 8 Homocoupling of Phenylboronic Acid to Give Biphenyl

Phenylboronic acid (0.488 g, 4 mmol), tetrabutylammonium acetate (1.204g, 4 mmol) and palladium(II) acetate (0.022 g, 0.01 mmol) were added toa stainless steel pressure reactor vessel. The vessel was charged withcarbon dioxide and was then pressurised to 3000 psi at a temperature of110° C. The reaction was allowed to proceed under these conditions for16 h. The vessel was cooled to 25° C., and the contents were vented intoethyl acetate (100 cm⁻³). The cell was rinsed out with further ethylacetate (50 cm³). Evaporation of the combined organic solvent andrecrystallisation of the crude product from hexane afforded biphenyl(0.028 g, 9%).

1. A palladium-catalysed carbon-carbon bond forming reaction incompressed carbon dioxide as a solvent wherein at least one of thereagents used in said reaction is bound to a solid polymer support.
 2. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to claim 1 wherein said reactionis selected from the group consisting of Heck, Suzuki, Sonogashira andStille reactions.
 3. A palladium-catalysed carbon-carbon bond formingreaction in compressed carbon dioxide as a solvent according to claim 1or claim 2 wherein said polymer-bound reagents are selected frompolymer-supported bases and polymer-supported solubilising ligands.
 4. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to claim 3 wherein saidpolymer-supported base is a polymer-supported amine base.
 5. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to claim 4 wherein saidpolymer-supported amine base is a polymer having supportedmonoalkylaminoalkyl groups or a polymer having supporteddialkylaminoalkyl groups wherein each alkyl group is the same ordifferent and has from 1 to 6 carbon atoms.
 6. A palladium-catalysedcarbon-carbon bond forming reaction in compressed carbon dioxide as asolvent according to any one of claims 3 to 5 wherein said supportingsolid polymer is selected from polystyrenes and macroreticular resins.7. A palladium-catalysed carbon-carbon bond forming reaction incompressed carbon dioxide as a solvent according to any one of claims 3to 6 wherein said polymer-supported base is selected fromdialkylaminoalkylpolystyrenes and dialkylamino-macroreticular resins. 8.A palladium-catalysed carbon-carbon bond forming reaction in compressedcart dioxide as a solvent according to claim 7 wherein saidpolymer-supported base is selected from diethylaminomethylpolystyrene,diethylaminomethyl-macroreticular resin anddisopropylmethylaminopolystyrene.
 9. A palladium-catalysed carbon-carbonbond forming reaction in compressed carbon dioxide as a solventaccording to claim 7 wherein said polymer-supported base isdiethylaminomethylpolystyrene.
 10. A palladium-catalysed carbon-carbonbond forming reaction in compressed carbon dioxide as a solventaccording to any one of claims 1 to 9 wherein said polymer-supportedsolubilising ligand is selected from polymer-supported phosphineligands.
 11. A palladium-catalysed carbon-carbon bond forming reactionin compressed carbon dioxide as a solvent according to claim 10 whereinsaid supporting polymer is selected from polystyrenes and macroreticularresins.
 12. A palladium-catalysed carbon-carbon bond forming reaction incompressed carbon dioxide as a solvent according to any one of claims 1to 11 wherein said phosphine ligands on said solid polymer supports areselected from phosphine ligands that have at least onefluoro-substituted aliphatic or aromatic substituent, and phosphineligands that do not have any fluorinated substituents but do have atleast one substituent selected from alkyl groups, cycloalkyl groups andaryl groups.
 13. A palladium-catalysed carbon-carbon bond formingreaction in compressed carbon dioxide as a solvent according to claim 12wherein said phosphine ligands on said solid polymer supports areselected from diarylphosphinoalkyl groups, dialkylphospinoalkyl groupsand dicycloalkylphospinoalkyl groups wherein each alkyl moiety has from1 to 6 carbon atoms, each cycloalkyl group has from 3 to 8 carbon atomsand each aryl group is a phenyl group that may optionally be substitutedwith at least one alkyl group having from 1 to 6 carbon atoms.
 14. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to claim 10 wherein saidpolymer-supported phosphine is selected from polystyrenes andmacroreticular resins having supported diphenylphosphinoalkyl groupswherein said alkyl groups have from 1 to 6 carbon atoms.
 15. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to claim 14 wherein saidpolymer-supported phosphine is diphenylphospinomethylpolystyrene.
 16. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to any one of claims 1 to 15wherein at least one of the substrates of the carbon-carbon bond formingreaction is bound to a solid polymer support.
 17. A palladium-catalysedcarbon-carbon bond forming reaction in compressed carbon dioxide as asolvent according to any one of claims 1 to 16 wherein said reaction isconducted as a continuous flow reaction.
 18. A palladium-catalysedcarbon-carbon bond forming reaction in compressed carbon dioxide as asolvent wherein said reaction is performed in the presence of atetra-alkylammonium acetate wherein each alkyl group is the same ordifferent and has from 1 to 6 carbon atoms.
 19. A palladium-catalysedcarbon-carbon bond forming reaction in compressed carbon dioxide as asolvent according to claim 18 wherein each all group of saidtetra-alkylammonium acetate is the same or different and has from 1 to 4carbon atoms.
 20. A palladium-catalysed carbon-carbon bond formingreaction in compressed carbon dioxide as a solvent according to claim 18wherein said tetra-alkylammonium acetate is selected fromtetraethylammonium acetate and tetra(n-butyl)ammonium acetate.
 21. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to claim 18 wherein saidtetra-alkylammonium acetate is tetra(n-butyl)ammonium acetate.
 22. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to any one of claims 18 to 21wherein said reaction is selected from the group consisting of Heck,Suzuki, Sonogashira and Stille reactions.
 23. A palladium-catalysedcarbon-carbon bond forming reaction in compressed carbon dioxide as asolvent according to any one of claims 18 to 22 wherein said reaction isconducted using a solubilising ligand selected from phosphine ligandsthat have at least one fluoro-substituted aliphatic or aromaticsubstituent, and phosphine ligands that do not have any fluorinatedsubstituents but, do have at least one substituent selected from alkylgroups, cycloalkyl groups and aryl groups.
 24. A palladium-catalysedcarbon-carbon bond forming reaction in compressed carbon dioxide as asolvent according to claim 23 wherein said phosphine ligands areselected from triarylphosphinoalkyl groups, trialkylphospinoalkyl groupsand tricycloalkylpbospinoalkyl groups wherein each alkyl moiety has from1 to 6 carbon atoms, each cycloalkyl group has from 3 to 8 carbon atomsand each aryl group is a phenyl group that may optionally be substitutedwith at least one alkyl group having from 1 to 6 carbon atoms.
 25. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to claim 23 wherein said phosphineligands are selected from tri(t-butyl)phosphine,tri(cyclohexyl)phosphine, tri(o-tolyl)phosphine and1′-diphenyl-phosphinobiphenyl.
 26. A palladium-catalysed carbon-carbonbond forming reaction in compressed carbon dioxide as a solventaccording to any one of claims 18 to 22 wherein said reaction isconducted using a polymer-supported solubilising ligand as defined inany one of claims 10 to
 15. 27. A palladium-catalysed carbon-carbon bondforming reaction in compressed carbon dioxide as a solvent according toany one of claims 18 to 22 wherein at least one of the substrates of thecarbon-carbon bond forming reaction is bound to a solid polymer support.28. A palladium-catalysed carbon-carbon bond forming reaction incompressed carbon dioxide as a solvent according to any one of claims 18to 27 wherein said reaction is conducted as a continuous flow reaction.29. A palladium-catalysed carbon-carbon bond forming reaction incompressed carbon dioxide as a solvent wherein said palladium catalystdoes not have any fluorinated phosphine ligands but does have at leastone phosphine ligand that has at least one substituent that is selectedfrom the group consisting of tert-alkyl groups having from 4 to 10carbon atoms, cycloalkyl groups having from 3 to 8 carbon atoms andphenyl groups which can be substituted with at least one alkyl grouphaving from 1 to 6 carbon atoms or 1′-diphenyl-phosphinobiphenyl.
 30. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to claim 29 wherein saidtert-alkyl substituents for said phosphine ligands are tert-butylgroups, said cycloalkyl substituents for said phosphine ligands arecyclohexyl groups and said optionally substituted phenyl groups for saidphosphine ligands are o-tolyl groups.
 31. A palladium-catalysedcarbon-carbon bond forming reaction in compressed carbon dioxide as asolvent according to claim 29 wherein said phosphines are selected fromtri(t-butyl)phosphine, tri(cyclohexyl)phosphine, tri(o-tolyl)phosphineand 1′-diphenylphosphinobiphenyl.
 32. A palladium-catalysedcarbon-carbon bond forming reaction in compressed carbon dioxide as asolvent according to claim 29 wherein said phosphine istri(z-butyl)phosphine.
 33. A palladium-catalysed carbon-carbon bondforming reaction in compressed carbon dioxide as a solvent according toany one of claims 29 to 32 wherein said reaction is selected from thegroup consisting of Heck, Suzuki, Sonogashira and Stille reactions. 34.A palladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to any one of claims 29 to 33wherein said reaction is performed in the presence of a base or otherreaction-promoting additive selected from diisopropylethylamine, cesiumcarbonate, diethylaminomethylpolystyrene, sodium acetate, sodiumtrifluoroacetate, triethylamine, tri-n-butylamine, perfluorinatedtrihexylamine, polystrenemethylammonium carbonate,tetramethylethylenediamine diamine (TMEDA), tetramethyl hexanediamine,and tetra-alkylammonium acetates wherein each alkyl group has from 1 to6 carbon atoms.
 35. A palladium-catalysed carbon-carbon bond formingreaction in compressed carbon dioxide as a solvent according to claim 34wherein said reaction is performed in the presence of a base selectedfrom tetramethyl hexanediamine and cesium carbonate.
 36. Apalladium-catalysed carbon-carbon bond forming reaction in compressedcarbon dioxide as a solvent according to claim 34 wherein said reactionis performed in the presence of a reaction-promoting additive selectedfrom tetra-alkylammonium acetates wherein each alkyl group has from 1 to6 carbon atoms.
 37. A palladium-catalysed carbon-carbon bond formingreaction in compressed carbon dioxide as a solvent according to any oneof claims 29 to 36 wherein at least one of the substrates of thecarbon-carbon bond forming reaction is bound to a solid polymer support.38. A palladium-catalysed carbon-carbon bond forming reaction incompressed carbon dioxide as a solvent according to any one of claims 29to 37 wherein said reactions is conducted as a continuous flow reaction.39. A palladium-catalysed Suzuki or Heck reaction in compressed carbondioxide as a solvent wherein both of the substrates being combined insaid reactions are boronic acids.